Combination therapy for treatment of cancer

ABSTRACT

The present invention relates to methods and compositions for the treatment of cancer. Some embodiments include methods of treating cancer comprising administering a chemotherapeutic agent associated with albumin, administering a second chemotherapeutic agent; and administering a third chemotherapeutic agent.

RELATED APPLICATIONS

This application, is a continuation of U.S. Ser. No. 14/117832 filedNov. 14, 2013 entitled “COMBINATION THERAPY FOR TREATMENT OF CANCER”which is the U.S. National Phase of PCT Application No.PCT/US2012/038111 entitled “COMBINATION THERAPY FOR TREATMENT OF CANCER”filed May 16, 2012, and published in English on Nov. 22, 2012 as WO2012/158776 which claims the benefit of U.S. Provisional Application No.61/487232 entitled “COMBINATION THERAPY FOR TREATMENT OF CANCER” filedMay 17, 2011, the disclosure of which is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates to methods and compositions for thetreatment of cancer. Some embodiments include methods of treating cancercomprising administering a chemotherapeutic agent associated with orbound to albumin, administering a second chemotherapeutic agent; andadministering a third chemotherapeutic agent.

BACKGROUND OF THE INVENTION

Breast cancer is the most common cancer among women (excluding basal andsquamous cell skin cancer) in the U.S. and is the second most commoncause of cancer death among women. In the year 2007, the estimated newcases of breast cancer among women in the U.S. is 178,480 and theestimated death from breast cancer is 40,460 (1).

Neoadjuvant chemotherapy for breast cancer is the use of chemotherapybefore definitive surgical therapy such as lumpectomy or mastectomy.Compared with adjuvant or postoperative chemotherapy, neoadjuvantchemotherapy allows higher rates of breast conservation withoutcompromising overall survival (2). In addition, neoadjuvant chemotherapypermits a unique opportunity to observe and evaluate tumor response totreatment and therefore, serving as an in vivo chemosensitivity assay.This may allow the tailoring of treatment for individual patients basedon their tumor response to a particular chemotherapy regimen (3-5). Thismay potentially enhance response and survival and at the same timereduce unnecessary toxicities.

Not only neoadjuvant chemotherapy does result in similar overallsurvival compared with adjuvant chemotherapy, it is also associated withless adverse toxicities (6). Compared with adjuvant chemotherapy,neoadjuvant chemotherapy is associated with significantly lessinfectious complications and cardiotoxicity (6). In addition, there issuggestive evidence that neoadjuvant chemotherapy may be superior toadjuvant chemotherapy on survival outcome (7). In contrast with adjuvantchemotherapy, there is currently no clear recommendation on neoadjuvantchemotherapy regimens. There is a need for improved therapies forcancer.

SUMMARY OF THE INVENTION

Some embodiments of the present invention include methods of treating acancer in a subject in need thereof comprising administering achemotherapeutic agent associated with or bound to albumin;administering a second chemotherapeutic agent; and administering a thirdchemotherapeutic agent.

In some embodiments, the chemotherapeutic agent associated with or boundto albumin is administered periodically.

In some embodiments, the chemotherapeutic agent associated with or boundto albumin the second chemotherapeutic agent and a thirdchemotherapeutic agent are administered on the same day and subsequentlythe chemotherapeutic agent associated with or bound to albumin isadministered, periodically without the second chemotherapeutic agent andthe third chemotherapeutic agent.

In some embodiments, on some occasions the chemotherapeutic agentassociated with or bound to albumin the second chemotherapeutic agentand a third chemotherapeutic agent are administered on the same day andon other occasions only the chemotherapeutic agent associated with orbound to albumin is administered.

In some embodiments, the chemotherapeutic agent associated with or boundto albumin comprises an agent selected from the group consisting ofpaclitaxel, docetaxel, and rapamycin.

In some embodiments, the chemotherapeutic agent associated with or boundto albumin is nab-paclitaxel (ABRAXANE®).

In some embodiments, the second chemotherapeutic agent comprises atopoisomerase inhibitor.

In some embodiments, the topoisomerase inhibitor is doxorubicin.

In some embodiments, the third chemotherapeutic agent comprises analkylating agent.

In some embodiments, the alkylating agent is cyclophosphamide.

In some embodiments, the chemotherapeutic agent associated with or boundto albumin is administered on days 1 and 8.

In some embodiments, the chemotherapeutic agent associated with or boundto albumin is administered on days 1, 8, 15.

In some embodiments, the chemotherapeutic agent associated with or boundto albumin is administered on days 1, 8, 15, and 22.

In some embodiments, the chemotherapeutic agent associated with or boundto albumin is administered on days 1, 8, 15, 22, and 28.

In some embodiments, the chemotherapeutic agent associated with or boundto albumin is administered on days 1, 8, and 22.

In some embodiments, the chemotherapeutic agent associated with or boundto albumin is administered at an interval of at least about 5 days.

In some embodiments, the chemotherapeutic agent associated with or boundto albumin is administered at an interval of at least about 6 days.

In some embodiments, the chemotherapeutic agent associated with or boundto albumin is administered at an interval of at least about 7 days.

In some embodiments, the periodic administration comprises at least 2cycles.

In some embodiments, the periodic administration comprises at least 5cycles.

In some embodiments, the chemotherapeutic agent associated with or boundto albumin the second chemotherapeutic agent and the thirdchemotherapeutic agent are administered, on the same day andsubsequently the administration of the chemotherapeutic agent associatedwith or bound to albumin is repeated for a plurality of cycles.

In some embodiments, the plurality of cycles for the subsequentadministration of the chemotherapeutic agent associated with or bound toalbumin comprises at least 2 cycles.

In some embodiments, the plurality of cycles for the subsequentadministration of the chemotherapeutic agent associated with or bound toalbumin comprises at least 5 cycles.

In some embodiments, each cycle for the subsequent administration of thechemotherapeutic agent associated with or bound to albumin comprises atleast about 5 days.

In some embodiments, each cycle for the subsequent administration of thechemotherapeutic agent associated with or bound to albumin comprises atleast about 6 days.

In some embodiments, each cycle for the subsequent administration of thechemotherapeutic agent associated with or bound to albumin comprises atleast about 7 days.

In some embodiments, each cycle for the subsequent administration of thechemotherapeutic agent associated with or bound to albumin comprises atleast about 1 week.

In some embodiments, at least about 100 mg/m² nab-paclitaxel (ABRAXANE®)is administered on day 1 and 8, at least about 50 mg/m² doxorubicin isadministered on day 1, and at least about 500 mg/m² cyclophosphamide isadministered on day 1.

Some embodiments also include administering Pegfilgrastim on day 9.

In some embodiments, the cancer is breast cancer.

In some embodiments, the cancer is HER2 negative breast cancer.

In some embodiments, the cancer is triple negative breast cancer.

In some embodiments, the dose of nab-paclitaxel (ABRAXANE®) is betweenabout 50 mg/m² and about 200 mg/m².

In some embodiments, the dose of nab-paclitaxel (ABRAXANE®) is selectedfrom the group consisting of 100 mg/m² and 150 mg/m2.

Some embodiments include use of a combination comprising achemotherapeutic agent associated with or bound to albumin, a secondchemotherapeutic agent, and a third chemotherapeutic agent for thetreatment of cancer.

In some embodiments, the chemotherapeutic agent associated with or boundto albumin is administered periodically.

In some embodiments, the chemotherapeutic agent associated with or boundto albumin the second chemotherapeutic agent and a thirdchemotherapeutic agent are administered on the same day and subsequentlythe chemotherapeutic agent associated with or bound to albumin isadministered periodically without the second chemotherapeutic agent andthe third chemotherapeutic agent.

In some embodiments, on some occasions the chemotherapeutic agentassociated with or bound to albumin the second chemotherapeutic agentand a third chemotherapeutic agent are administered on the same day andon other occasions only the chemotherapeutic agent associated with orbound to albumin is administered.

In some embodiments, the chemotherapeutic agent associated with or boundto albumin comprises an agent selected from the group consisting ofpaclitaxel, docetaxel, and rapamycin.

In some embodiments, the chemotherapeutic agent associated with or boundto albumin is nab-paclitaxel (ABRAXANE®).

In some embodiments, the second chemotherapeutic agent comprises atopoisomerase inhibitor.

In some embodiments, the topoisomerase inhibitor is doxorubicin.

In some embodiments, the third chemotherapeutic agent comprises analkylating agent.

In some embodiments, the alkylating agent is cyclophosphamide.

In some embodiments, the chemotherapeutic agent associated with or boundto albumin is administered on days 1 and 8.

In some embodiments, the chemotherapeutic agent associated with or boundto albumin is administered on days 1, 8, 15.

In some embodiments, the chemotherapeutic agent associated with or boundto albumin is administered on days 1, 8, 15, and 22.

In some embodiments, the chemotherapeutic agent associated with or boundto albumin is administered on days 1, 8, 15, 22, and 28.

In some embodiments, the chemotherapeutic agent associated with or boundto albumin is administered on days 1, 8, and 22.

In some embodiments, the chemotherapeutic agent associated with or boundto albumin is administered at an interval of at least about 5 days.

In some embodiments, the chemotherapeutic agent associated with or boundto albumin is administered at an interval of at least about 6 days.

In some embodiments, the chemotherapeutic agent associated with or boundto albumin is administered at an interval of at least about 7 days.

In some embodiments, the periodic administration comprises at least 2cycles.

In some embodiments, the periodic administration comprises at least 5cycles.

In some embodiments, the chemotherapeutic agent associated with or boundto albumin the second chemotherapeutic agent and the thirdchemotherapeutic agent are administered on the same day and subsequentlythe administration of the chemotherapeutic agent associated with orbound to albumin is repeated for a plurality of cycles.

In some embodiments, the plurality of cycles for the subsequentadministration of the chemotherapeutic agent associated with or bound toalbumin comprises at least 2 cycles.

In some embodiments, the plurality of cycles for the subsequentadministration of the chemotherapeutic agent associated with or bound toalbumin comprises at least 5 cycles.

In some embodiments, each cycle for the subsequent administration of thechemotherapeutic agent associated with or bound, to albumin comprises atleast about 5 days.

In some embodiments, each cycle for the subsequent administration of thechemotherapeutic agent associated with or bound to albumin comprises atleast about 6 days.

In some embodiments, each cycle for the subsequent administration of thechemotherapeutic agent associated with or bound to albumin comprises atleast about 7 days.

In some embodiments, each cycle for the subsequent administration of thechemotherapeutic agent associated with or bound to albumin comprises atleast about 1 week.

In some embodiments, at least about 100 mg/m² nab-paclitaxel (ABRAXANE®)is administered on day 1 and 8, at least about 50 mg/m² doxorubicin isadministered, on day 1, and at least about 500 mg/m² cyclophosphamide isadministered on day 1.

Some embodiments also include administering Pegfilgrastim on day 9.

In some embodiments, the cancer is breast cancer.

In some embodiments, the cancer is HER2 negative breast cancer.

In some embodiments, the cancer is triple negative breast cancer.

In some embodiments, the dose of nab-paclitaxel (ABRAXANE®) is betweenabout 50 mg/m² and about 200 mg/m².

In some embodiments, the dose of nab-paclitaxel (ABRAXANE®) is selectedfrom the group consisting of 100 mg /m² and 150 mg/m².

DETAILED DESCRIPTION

The present invention relates to methods and compositions for thetreatment of cancer. Some embodiments include methods of treating cancercomprising administering a chemotherapeutic agent associated with orbound to albumin, administering a second chemotherapeutic agent; andadministering a third chemotherapeutic agent.

Currently, there is no cure for patients with metastatic breast cancer.Therefore, treating patients with early stage breast cancer, eitherbefore surgery (neoadjuvant) or after surgery (adjuvant) is an importantstrategy to reduce the chance of cancer recurrence locally or distally,thereby reducing morbidity and mortality.

Triple-negative breast cancer includes breast cancers that do notexpress the genes for estrogen receptor (ER), progesterone receptor (PR)or Her2/neu. This subtype of breast cancer is clinically characterizedas more aggressive and, less responsive to standard treatment andassociated poorer overall patient prognosis. Basal-like or triplenegative breast cancer cells express high levels of Secreted protein,acidic, cysteine-rich (SPARC) protein, also known as osteonectin, whichbinds and entraps albumin. Overexpression of SPARC protein has also beenreported in many human cancers such as, prostate and colon cancers.

Expression of SPARC protein by cancer cells can be useful to targetchemotherapeutic agents to a tumor. In an example pathway, activation ofa specific receptor (gp60) on the endothelial cell wall in turnactivates the protein, caveolin-1. Caveolin-1 can initiate the formationof caveolae which can transport materials, such as chemotherapeuticagents associated with albumin to the tumor interstitium (17). SPARCprotein expressed by the tumor may bind and entrap the chemotherapeuticagents associated with or bound to albumin (18). Nab-paclitaxel(ABRAXANE®) is an example of a chemotherapeutic agent associated withalbumin.

There is currently no clear recommendation on neoadjuvant chemotherapyregimens. Doxorubicin (Adriamycin) and taxanes are active drugs againstbreast cancer. A regimen of Taxotere, Adriamycin, and Cyclophosphamide(TAC) administered every three weeks for 6 cycles, is among the mostactive regimens in the adjuvant and neoadjuvant settings (3, 13, 14).However, the pathologic complete response rate, which is a surrogate forlong term survival, is quite low for this regimen. A regimen ofnab-paclitaxel (ABRAXANE®) administered weekly can provide an increasedpositive response in patients with lower side effects, compared to aregimen of administering Taxotere every 3 weeks. Some methods describedherein include regimens including administration of Nab-paclitaxel,Adriamycin, and Cytoxan (NAC).

The TAC regimen (docetaxel, doxorubicin, and cyclophosphamide) is amongthe most active drug combinations in the adjuvant and neoadjuvantsettings. A weekly nab-paclitaxel is superior to every-three weekdocetaxel in both efficacy and toxicity in patients with metastaticbreast cancer. Provided herein are results of a single center phase Istudy in which nab-paclitaxel replaces docetaxel in the conventional TACregimen.

Albumin-Associated or Albumin-Bound Chemotherapeutic Agents

Some embodiments of the methods and compositions described hereininclude chemotherapeutic agents associated with or bound to albumin.Examples of chemotherapeutic agents which may be associated with orbound to albumin include Vinca alkaloids (e.g., Vinblastine,Vincristine, Vinflunine, Vindesine, Vinorelbine) Taxanes (e.g.,Cabazitaxel, Docetaxel, Larotaxel, Ortataxel, Paclitaxel, Tesetaxel) andEpothilones (e.g., Ixabepilone), dihydrofolate reductase inhibitors(e.g., Aminopterin, Methotrexate, Pemetrexed, Pralatrexate), thymidylatesynthase inhibitors (e.g., Raltitrexed, Pemetrexed), adenosine deaminaseinhibitors (e.g., Pentostatin), ribonucleotide reductase inhibitors(e.g., Cladribine, Clofarabine, Fludarabine), thiopurine (e.g.,Thioguanine, Mercaptopurine), thymidylate synthase inhibitors (e.g.,Fluorouracil, Capecitabine, Tegafur, Carmofur, Floxuridine), DNApolymerase inhibitors (e.g., Cytarabine), ribonucleotide reductaseinhibitors (e.g., Gemcitabine), hypomethylating agents (e.g.,Azacitidine, Decitabine), ribonucleotide reductase inhibitors (e.g.,Hydroxycarbamide), Topoisomerase inhibitors (e.g., Camptothecin,Topotecan, Irinotecan, Rubitecan, Belotecan, Etoposide, Teniposide,Anthracyclines such as Aclarubicin, Daunorubicin, Doxorubicin,Epirubicin, Idarubicin, Amrubicin, Pirarubicin, Valrubicin, Zorubicin,and Anthracenediones such as Mitoxantrone, Pixantrone), Alkylatingagents (e.g., Mechlorethamine, Cyclophosphamide such as Ifosfamide andTrofosfamide, Chlorambucil such as Melphalan, Prednimustine, as well asBendamustine, Uramustine, Nitrosoureas such as Carmustine, Lomustine,Fotemustine, Nimustine. Ranimustine. Streptozocin, Alkyl sulfonates suchas Busulfan, Mannosulfan, and Treosulfan, and Aziridines such asCarboquone, ThioTEPA, Triaziquone, and Triethylenemelamine), Platinums(e.g., Carboplatin, Cisplatin, Nedaplatin, Oxaliplatin, Triplatintetranitrate, and Satraplatin), Hydrazines (e.g., Procarbazine),Triazenes (e.g., Dacarbazine, Temozolomide), Altretamine, andMitobronitol, Intercalation agents (e.g., Actinomycin, Bleomycin,Mitomycin, Plicamycin). More examples of chemotherapeutic agents includeAminolevulinic acid, Efaproxiral, Porphyrin derivatives (e.g., Porfimersodium, Talaporfm, Temoporfin, Verteporfin), Enzyme inhibitors (e.g.,Tipifarnib, Alvocidib, Seliciclib, Bortezomib, Anagrelide, Tiazofurine,Masoprocol, Olaparib, Vorinostat, Romidepsin), Atrasentan, Bexarotene,Testolactone, Amsacrine, Trabectedin, Alitretinoin, Tretinoin, Arsenictrioxide, Celecoxib, Demecolcine, Elesclomol, Elsamitrucin, Etoglucid,Lonidamine, Lucanthone, Mitoguazone, Mitotane, Oblimersen, Omacetaxinemepesuccinate, Everolimus, and Temsirolimus.

In some embodiments, the chemotherapeutic agent and albumin comprise ananoparticle. Examples nanoparticle include nab-paclitaxel (ABRAXANE®).Nab-paclitaxel (ABRAXANE®) is a novel biologically interactivealbumin-bound paclitaxel combining a protein with a chemotherapeuticagent in the particle form. Nab-paclitaxel (ABRAXANE®) is an example ofan interactive nanoparticle leveraging thisgp-60/caveolin-1/caveolae/SPARC pathway to increase intra-tumoralconcentration of the drug and reducing toxic drug in normal tissue.

In some embodiments of the methods and uses provided herein, two or moreof the chemotherapeutic agents described herein can be administered to asubject in need thereof. In some embodiments, three or more of thechemotherapeutic agents described herein can be administered to asubject in need thereof. In some such embodiments, at least one of thechemotherapeutic agents administered to the subject comprises achemotherapeutic agent associated with or bound to albumin.

Preclinical and Clinical Studies With Nab-Paclitaxel (ABRAXANE®)

Preclinical studies comparing nab-paclitaxel (ABRAXANE®) to Taxoldemonstrated, lower toxicities, with a maximum tolerated dose (MTD)approximately 50% higher for nab-paclitaxel (ABRAXANE®) compared toTaxol. At equal doses there was less myelosuppression and improvedefficacy in a xenograft tumor model of human mammary adenocarcinoma. Atequitoxic doses of paclitaxel, nab-paclitaxel (ABRAXANE®) was found tobe markedly more efficacious than Taxol (19).

Every 3 Weeks Schedule

In a phase I study, the MTD of nab-paclitaxel (ABRAXANE®) was determinedto be 300 mg/m² by 30 minute infusion every 3 weeks, withoutpremedication or G-CSF support (20). No severe hypersensitivityreactions occurred with nab-paclitaxel (ABRAXANE®) despite the absenceof premedication. Dose-limiting toxicities included sensory neuropathy,stomatitis, and superficial keratopathy, which occurred at a dose of 375mg/m².

Two multicenter phase II studies have evaluated 2 dose levels ofnab-paclitaxel (ABRAXANE®) (300 mg/m², n=63, and 175 mg/m², n=43) inpatients with metastatic breast cancer (21, 22). The overall responserates in these 2 phase II trials were 40% (95% CI 25-54%) for the 175mg/m² dose, and 48% (95% CI 35-60%) for the 300 mg/m² dose. Of 39patients receiving 300 mg/m² as first-line therapy for metastatic breastcancer, 64% (95% CI 49-79%) responded. This was contrasted with a 45%response rate in similar patients at the lower dose level. Grade 4neutropenia was noted in 24% of patients at the higher dose level,occurred primarily during the first cycle and resolved rapidly.

A Phase III trial in patients with metastatic breast cancer comparednab-paclitaxel (ABRAXANE®) 260 mg/m² to Taxol 175 mg/m² given every 3weeks (23). Efficacy analyses were based on the intent-to-treat (ITT)population. The overall response rate (ORR) was significantly greaterfor nab-paclitaxel (ABRAXANE®) than for Taxol for all patients (33% v19%, respectively; P=0.001), patients who received first-line therapy(42% v 27%, respectively; P=0.029), patients who received second-line orgreater therapy (27% v 13%, respectively; P=0.006), and patients who hadreceived prior anthracycline therapy in either the adjuvant/metastaticsetting (34% v 18%, respectively; P=0.002) or the metastatic settingonly (27% v 14%, respectively; P=0.010). Tumor response rate was alsosignificantly higher for nab-paclitaxel (ABRAXANE®) than for Taxol inpatients with visceral dominant lesions (34% v 19%, respectively;P=0.002) and in patients aged younger than 65 years (34% v 19%,respectively; P<0.001). ORR also was greater for nab-paclitaxel(ABRAXANE®) compared with standard paclitaxel in patients withnonvisceral dominant lesions (34% v 19%, respectively) and in patients≧65 years old (27% v 19%, respectively), but the results did not reachstatistical significance because of the small number of patients inthese subsets.

Median time to tumor progression (TTP) was significantly longer withnab-paclitaxel (ABRAXANE®) than with Taxol for all patients (23.0 v 16.9weeks, respectively; hazard, ratio [HR]=0.75; P=0.006). There was atrend, for greater median survival for all patients treated withnab-paclitaxel (ABRAXANE®) than with Taxol (65.0 v 55.7 weeks,respectively; P=0.374). Although no difference in survival was observedin first-line patients, the difference was statistically significant inpatients who received nab-paclitaxel (ABRAXANE®), compared with Taxol,as second-line or greater therapy (56.4 v 46.7 weeks, respectively;HR=0.73; P .024) (23).

The incidence of hypersensitivity reactions (any grade) was low for botharms (1% for nab-paclitaxel (ABRAXANE®) and 2% for Taxol). No severe(grade 3 or 4) treatment-related hypersensitivity reactions occurred inany of the patients in the nab-paclitaxel (ABRAXANE®) group despite theabsence of premedication. In contrast, grade 3 hypersensitivityreactions occurred in the Taxol group despite standard premedication(chest pain, two patients; allergic reaction, three patients). Perprotocol, corticosteroids and antihistamines were not administeredroutinely to patients in the nab-paclitaxel (ABRAXANE®) group; however,premedication was administered for emesis, myalgia/arthralgia, oranorexia in 18 patients (8%) in the nab-paclitaxel (ABRAXANE®) group in2% of the treatment cycles, whereas 224 patients (>99%) in the Taxolgroup received premedication in 95% of the cycles.

Although the patients in the nab-paclitaxel (ABRAXANE®) group receivedan average paclitaxel dose-intensity 49% greater than that received bypatients in the Taxol group, the incidence of treatment-related grade 4neutropenia was significantly lower in the nab-paclitaxel (ABRAXANE®)group than in the Taxol group (9% v 22%, respectively; P<0.001), with ahigher mean neutrophil nadir (1.67 v 1.31×10⁹/L, respectively; P=0.046),suggesting that polyethylated castor oil may have contributed to thistoxicity in patients who received standard paclitaxel.

As expected with a higher dose of paclitaxel, treatment-related grade 3sensory neuropathy occurred more frequently in the nab-paclitaxel(ABRAXANE®) arm than in the Taxol arm (10% v 2%, respectively; P<0.001);however, these episodes improved with interruption, of treatment tograde 2 or 1 in a median 22 days and were easily managed with treatmentinterruption and dose reduction. By day 28 after its first occurrence,the number of patients with persistent grade 3 sensory neuropathy wasthe same (n=4) in both study arms. No episodes of motor neuropathy orgrade 4 sensory neuropathy were reported in either group.

The only clinical chemistry value that was notably different between thetwo treatment arms was higher serum glucose levels in the Taxol—treatedpatients, who also had a higher incidence of hyperglycemia reported asan adverse effect (AE) compared with nab-paclitaxel (ABRAXANE®)—treatedpatients (7% v 1% respectively; P=0.003).

Subgroup analyses revealed that the safety profiles of nab-paclitaxel(ABRAXANE®) and Taxol in patients who received the drugs as first-linetherapy were similar to those in the overall study population. Insubgroup analyses by age, the reported AEs were similar in patients lessthan 65 years old and patients ≧65 years old in both groups. Of thepatients ≧65 years old, the incidences of the following AEs were notablylower in the nab-paclitaxel (ABRAXANE®) group than in the Taxol group:neutropenia (23% v 59%, respectively), leukopenia (10% v 31%,respectively), nausea (20% v 38%, respectively), hyperglycemia (0% v19%, respectively), and flushing (0% v 16%, respectively). These dataindicate no additional safety concerns for nab-paclitaxel (ABRAXANE®) inpatients ≧65 years old compared with younger patients.

Six patients (3%) in the nab-paclitaxel (ABRAXANE®) group and eightpatients (4%) in the standard paclitaxel group died during the study,all as a result of disease progression. No treatment-related deathsoccurred in the nab-paclitaxel (ABRAXANE®) group; one patient (<1%) inthe Taxol group died of multiorgan failure, which was considered by theinvestigator to be possibly related to treatment but may also have beena result of sepsis and/or progressive disease.

Weekly for 3 Weeks, Every 4 Weeks Schedule

Thirty-nine patients were enrolled into A Phase I study ofnab-paclitaxel (ABRAXANE®) administered weekly for 3 weeks followed by a1 week rest in patients with advanced solid tumors (24). The MTDs forheavily and lightly pre-treated patients were 100 and 150 mg/m2respectively. Dose limiting toxicities included grade 4 neutropenia andgrade 3 sensory neuropathy. Premedication was not required, andunexpected, non-taxane associated toxicities were not observed.

In a Phase II trial in heavily pretreated patients withtaxane-refractory metastatic breast cancer, objective antitumorresponses occurred in 15% of women treated with nab-paclitaxel(ABRAXANE®) 100 mg/m2 on this schedule (25). Nab-paclitaxel (ABRAXANE®)weekly regimen was well tolerated. 91% of patients were treated at thefull dose of 100 mg/m2 of nab-paclitaxel (ABRAXANE®) without dosereductions. Based on the activity and low toxicity documented with thenab-paclitaxel (ABRAXANE®) 100 mg/m2 weekly regimen, this study wasexpanded to evaluate the efficacy and safety/tolerability of a higherdose of nab-paclitaxel (ABRAXANE®) 125 mg/m² weekly regimen in 75additional patients. Results of this dose-finding study confirm the doseof nab-paclitaxel (ABRAXANE®) 100 mg/m² as the appropriate dose forfurther study in this patient population (26).

Weekly Schedule

The NSABP studied the administration of nab-paclitaxel (ABRAXANE®) in aneoadjuvant setting to patients with locally advanced breast cancer at adose of 100 mg/m² weekly for 12 weeks, with no break (27). Four cyclesof FEC were administered sequentially based on patients' HER2 status:HER2 negative patients received FEC-100 (F: 500 mg/m², E: 100 mg/m², C:500 mg/m² Q3 weeks) and HER2 positive patients received weeklytrastuzumab in addition to FEC-75 (F: 500 mg/m², E: 75 mg/m², C: 500mg/m² Q3 weeks). Weekly trastuzumab was permitted during nab-paclitaxel(ABRAXANE®) and FEC-75 treatment at the discretion of the investigator.The primary objective of the trial was to determine the pathologiccomplete response rate (pCR) in the breast. At the time of initialreport at SABCS 2006, 65 patients had been entered on study and wereevaluable for cCR and safety. Following 12 weeks of nab-paclitaxel(ABRAXANE®), a clinical complete response rate (cCR) of 32% was noted.The therapy was well tolerated, with 48/65 patients receiving 12 dosesin 12 weeks and 13/65 receiving 12 doses in 13-14 weeks. The incidenceof peripheral (sensory) neuropathy was low (11% grade 2 and 5% grade 3)as was neutropenia (3% grade 3 and no grade 4). The authors concludedthat the administration of nab-paclitaxel (ABRAXANE®) 100 mg/m²weekly×12 was both effective and tolerable.

A recent phase II study has also demonstrated that weekly nab-paclitaxel(ABRAXANE®) is superior to every-three week Taxotere in both efficacyand toxicity profile, in the treatment of patients with advanced ormetastatic breast cancer (28). The rate of grade 4 neutropenia was 75%in the Taxotere group, compared to only 5% of the weekly nab-paclitaxel(ABRAXANE®) groups. Therefore, the use of growth factor support such asNeulasta that is often employed upfront in the TAC regimen (Taxotere,Adriamycin, Cyclophosphamide) may be omitted or reduced when Taxotere isreplaced by nab-paclitaxel (ABRAXANE®). This may also help reduce thetoxicity and overall cost of treatments (Neulasta is an expensive drugand adds considerably to the cost of treatments).

Commercial Chemotherapy

Doxorubicin and cyclophosphamide are commercially available drugs thatare commonly used, in the treatment of breast cancer. See e.g., thePhysicians' Desk Reference, incorporated herein by reference, in itsentirety.

Method for Treating Cancer

Some embodiments include methods of treating a cancer in a subject inneed thereof. In some embodiments, the cancer is breast cancer. In someembodiments, the cancer is HER2 negative breast cancer. In someembodiments, the cancer is triple negative breast cancer. Some suchmethods include administering a chemotherapeutic agent associated withor bound to albumin, administering a second chemotherapeutic agent; andadministering a third chemotherapeutic agent. In some embodiments, thechemotherapeutic agent associated with or bound to albumin isadministered periodically. In some embodiments, the chemotherapeuticagent associated with or bound to albumin comprises an agent selectedfrom the group consisting of paclitaxel, docetaxel, and rapamycin. Inparticular embodiments, the chemotherapeutic agent associated with orbound to albumin is nab-paclitaxel (ABRAXANE®).

In some embodiments, the second chemotherapeutic agent comprises atopoisomerase inhibitor. Examples of topoisomerase inhibitors aredescribed herein and can include doxorubicin. In some embodiments, thethird chemotherapeutic agent comprises an alkylating agent. Examples ofalkylating agents are described herein and can include cyclophosphamide.

In some embodiments, the chemotherapeutic agent associated with or boundto albumin is administered on days 1 and 8, or on, days 1, 8, 15, or ondays 1, 8, 15, and 22, or on days 1, 8, 15, 22, and 28, or on days 1, 8,and 22. In some embodiments, the chemotherapeutic agent associated withor bound to albumin is administered at an interval of at least about 2days, at least about 3 days, at least about 4 days, at least about 5days, at least about 6 days, at least about 7 days, at least about 8days, at least about 9 days, and at least about 10 days. In someembodiments, the administration of the chemotherapeutic agent associatedwith or bound to albumin; the administration of the secondchemotherapeutic agent; and/or the administration of the thirdchemotherapeutic agent are repeated for a plurality of cycles. In someembodiments, the plurality of cycles is at least 2, 3, 4, 5, 6, 7, 8, 9,or 10 cycles.

In some embodiments, the dose of a chemotherapeutic agent associatedwith or bound to albumin, such as nab-paclitaxel (ABRAXANE®), is betweenabout 50 mg/m² and about 200 mg/m². In some embodiments, the dose of achemotherapeutic agent associated with or bound to albumin, such asnab-paclitaxel (ABRAXANE®), is selected from the group consisting ofabout 100 mg/m² and about 150 mg/m².

In some embodiments, at least about 100 mg/m² nab-paclitaxel (ABRAXANE®)is administered on day 1 and 8, at least about 50 mg/m² doxorubicin isadministered on day 1, and at least about 500 mg/m² cyclophosphamide isadministered on day 1. Some such embodiments also include, administeringPegfilgrastim. In some embodiments, Pegfilgrastim is administered on day9.

EXAMPLES Example 1

Phase I Study of Neoadjuvant Chemotherapy with Nanoparticle AlbuminBound Paclitaxel, Doxorubicin and Cyclophosphamide

A Phase I study of neoadjuvant chemotherapy with nanoparticle albuminbound paclitaxel, doxorubicin, and cyclophosphamide (NAC) in patientswith stages II-III HER-2 negative breast, cancer was carried out.

Background: The TAC regimen (docetaxel, doxorubicin, andcyclophosphamide) is among the most active drug combinations in theadjuvant and neoadjuvant settings. A weekly nab-paclitaxel is superiorto every-three week docetaxel in both efficacy and toxicity in patientswith metastatic breast cancer. Provided herein are results of a singlecenter phase I study in which nab-paclitaxel replaces docetaxel in theconventional TAC regimen.

Methods: Women with HER-2 negative stages II-III breast cancer wereenrolled. Eligible patients received 6 cycles of the NAC regimen:nab-paclitaxel (100-150 mg/m², days 1 and 8), doxorubicin (50 mg /m²,day 1), and cyclophosphamide (500 mg/m², day 1). Peg-filgrastim wasgiven on day 9. Table 1 shows nab-paclitaxel (ABRAXANE®) dose schedules.

TABLE 1 nab-paclitaxel Dose level (ABRAXANE ®) dose (mg/m²) Doseschedule (days) −1 100 1, 8, rest 0 100 1, 8, 15, 22, 29, rest 1 150 1,8, rest, 22, 29, rest 2 150 1, 8, 15, 22, 29, rest

Results: Sixteen patients enrolled in the study, one of which was ascreen failure. Median tumor size was 6 cm. Median age was 54 years(40-69). ER+ tumors accounted for 53%, and 47% were triple negative.There were two inflammatory breast cancers. After the first threepatients on dose level 0 (nab-paclitaxel of 100 mg/m², weekly 5 on 1off, Q 6 weeks) experienced several dose delays because of grades 3 and4 neutropenia, the protocol was amended such that dose level −1(nab-paclitaxel of 100 mg/m², weekly 2 on 1 off, Q 3 weeks) would be thenew starting point and there would be no further dose escalation. Therewas no dose limiting toxicity (DLT). To date, a total of 57 cycles ofdose level −1 were given. 43.8% required dose delay. There were twoepisodes of febrile neutropenia. The pathologic complete response (pCR)by physical examination was 93.3%. One patient had a minimal response.The median number of cycles required before a pCR was 2. Even though pCRwas not a primary end point, we observed a very favorable pCR rate.Eight patients already underwent surgery. The pCR rate for this groupwas 50%. Another patient had a near pCR, with microscopic residualdisease. The pCR for the 4 triple negative patients was 100%.

Conclusions: This single center phase I study demonstrated safety anddramatic activity for the neoadjuvant NAC regimen in patients withstages II-III HER-2 negative breast cancer. This regimen was highlyeffective with impressive clinical and pathologic complete responses.

Example 2 Determination of Dosage Regimens

Other dosage regimens for chemotherapy with a combination of two or moreof the chemotherapeutic agents described herein, such as nanoparticlealbumin bound paclitaxel, doxorubicin, and/or cyclophosphamide (NAC),can be tested in patients, such as patients with stages II-III HER-2negative breast cancer. A series of studies are carried out with acombination of different chemotherapeutic agents. In each study, theperiod of providing a particular chemotherapeutic agent is different,for example, the particular chemotherapeutic agent is periodicallyadministered to a patient at an interval of 1 day, 2 days, 3 days, 4days, 5 days, 6 days, 7 days, 8 days, 9 days, or 10 days, or 1 week, 2weeks, 3 weeks, or 4 weeks. The pCR for each study group is determined.

Likewise, the period of providing the second and/or thirdchemotherapeutic agent may be varied and the second and/or thirdchemotherapeutic agents may be administered simultaneously with, on thesame day as, or on a different day as the first or secondchemotherapeutic agent in order to identify a treatment regimen thatprovides desirable results. In addition, regimens in which, one or moreof the chemotherapeutic agents are administered one or more times andthe subsequent administrations of those chemotherapeutic agentsdiscontinued while administration, of the remaining one or morechemotherapeutic agents is continued, may be evaluated to identifyregimens that provide desirable results.

Using particular regimens, the pCR is at least 30%, 40, 50%, 60%, 70%,80%, 90% or 95%. The optimum period for providing the particularchemotherapeutic agent in combination with at least one otherchemotherapeutic agent is determined.

The above description discloses several compositions and methods of thepresent invention. This invention is susceptible to modifications in themethods and materials, as well as alterations in the fabrication methodsand equipment. Such modifications will become apparent to those skilledin the art from a consideration of this disclosure or practice of theinvention disclosed herein. Consequently, it is not intended that thisinvention be limited to the specific embodiments disclosed herein, butthat it cover all modifications and alternatives coming within the truescope and spirit of the invention.

All references cited herein including, but not limited to, published andunpublished applications, patents, and literature references, areincorporated herein by reference in their entirety and are hereby made apart of this specification. To the extent publications and patents orpatent applications incorporated by reference contradict the disclosurecontained in the specification, the specification is intended tosupersede and/or take precedence over any such contradictory material.

The term “comprising” as used herein is synonymous with “including,”“containing,” or “characterized by,” and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps.

The following references are incorporated herein by reference in theirentireties.

REFERENCES

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1. A method of treating a cancer in a subject in need thereofcomprising: administering a chemotherapeutic agent associated with orbound to albumin; administering a second chemotherapeutic agent; andadministering a third chemotherapeutic agent.
 2. The method of claim 1,wherein the chemotherapeutic agent associated with or bound to albuminis administered periodically.
 3. The method of claim 1, wherein thechemotherapeutic agent associated with or bound to albumin the secondchemotherapeutic agent and a third chemotherapeutic agent areadministered on the same day and subsequently the chemotherapeutic agentassociated with or bound to albumin is administered periodically withoutthe second chemotherapeutic agent and the third chemotherapeutic agent.4. The method of claim 1, wherein on some occasions the chemotherapeuticagent associated with or bound to albumin the second chemotherapeuticagent and a third chemotherapeutic agent are administered on the sameday and on other occasions only the chemotherapeutic agent associatedwith or bound to albumin is administered.
 5. The method of claim 1,wherein the chemotherapeutic agent associated with or bound to albumincomprises an agent selected from the group consisting of paclitaxel,docetaxel, and rapamycin.
 6. The method of claim 1, wherein thechemotherapeutic agent associated with or bound to albumin is Abraxane.7. The method of claim 1, wherein the second chemotherapeutic agentcomprises a topoisomerase inhibitor.
 8. The method of claim 7, whereinthe topoisomerase inhibitor is doxorubicin.
 9. The method of claim 1,wherein the third chemotherapeutic agent comprises an alkylating agent.10. The method of claim 9, wherein the alkylating agent iscyclophosphamide.
 11. The method of claim 1, wherein thechemotherapeutic agent associated with or bound to albumin isadministered on days 1 and
 8. 12. The method of claim 1, wherein thechemotherapeutic agent associated with or bound to albumin isadministered on days 1, 8,
 15. 13. (canceled)
 14. (canceled)
 15. Themethod of claim 1, wherein the chemotherapeutic agent associated with orbound to albumin is administered on days 1, 8, and
 22. 16. The method ofclaim 1, wherein the chemotherapeutic agent associated with or bound toalbumin is administered at an interval of at least about 5 days. 17.(canceled)
 18. (canceled)
 19. The method of claim 2, wherein theperiodic administration comprises at least 2 cycles.
 20. (canceled) 21.The method of claim 3, wherein the chemotherapeutic agent associatedwith or bound to albumin the second chemotherapeutic agent and the thirdchemotherapeutic agent are administered on the same day and subsequentlythe administration of the chemotherapeutic agent associated with orbound to albumin is repeated for a plurality of cycles.
 22. (canceled)23. (canceled)
 24. The method of claim 21, wherein each cycle for thesubsequent administration of the chemotherapeutic agent associated withor bound to albumin comprises at least about 5 days.
 25. (canceled) 26.(canceled)
 27. (canceled)
 28. The method of claim 1, wherein at leastabout 100 mg/m² Abraxane is administered on day 1 and 8, at least about50 mg/m² doxorubicin is administered on day 1, and at least about 500mg/m² cyclophosphamide is administered on day
 1. 29. The method of claim28, further comprising administering Pegfilgrastim on day
 9. 30. Themethod of claim 1, wherein said cancer is breast cancer.
 31. The methodof claim 1, wherein the cancer is HER2 negative breast cancer.
 32. Themethod of claim 1, wherein the cancer is triple negative breast cancer.33. The method of claim 6, wherein the dose of Abraxane is between about50 mg/m² and about 200 mg/m².
 34. The method of claim 6, wherein thedose of Abraxane is selected from the group consisting of 100 mg/m² and150 mg/m^(2.)